fecal microbiota transplant: a novel biological...
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Citation for final published version:
Innes, Andrew J., Mullish, Benjamin H., Fernando, Fiona, Adams, George, Marchesi, Julian R.,
Apperley, Jane F., Brannigan, Eimear, Davies, Frances and Pavlu, Jiri 2017. Faecal microbiota
transplant: a novel biological approach to extensively drug-resistant organism-related non-relapse
mortality [Letter to the Editor]. Bone Marrow Transplantation 52 (10) , pp. 1452-1454.
10.1038/bmt.2017.151 file
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1
Fecal microbiota transplant: A novel biological approach to extensively 1
drug-resistant organism-related non-relapse mortality. 2
Andrew J Innes1,2, Benjamin H Mullish3, Fiona Fernando2, George Adams2, Julian R 3
Marchesi3,4, Jane F Apperley1,2, Eimear Brannigan5, Frances Davies5 and Jiri Pavlů1,2 4
5
1 Centre for Hematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital 6
Campus, Du Cane Road, London, W12 0NN 7
2 Department of Hematology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du 8
Cane Road, London, W12 0HS 9
3 Division of Digestive Diseases, Department of Surgery and Cancer, Faculty of Medicine, Imperial 10
College Lo do , St Mary’s Hospital Ca pus, South Wharf Road, Paddi gto , Lo do , W NY, UK 11
4 Division of Organisms and Environment, School of Biosciences, Cardiff University, Cardiff, UK 12
5 Department of Infectious diseases and Immunity, Imperial College Healthcare NHS Trust, 13
Hammersmith Hospital, Du Cane Road, London, W12 0HS 14
Running Title: FMT: A biological approach to XDRO 15
16
Key Words: Hematopoetic cell transplantation, non-relapse mortality, supportive care, extreme drug 17
resistant bacteria, multi-drug resistant bacteria, carbapenemase-producing Enterobacteriaceae 18
(CPE) 19
20
Corresponding author: 21
Jiri Pavlů 22
Imperial College NHS Trust 23
Hammersmith Hospital 24
Du Cane Road 25
London, W12 0NN 26
Tel 0203 313 8117 27
Fax 0203 313 3965 28
30
Conflict-of-interest disclosure: The authors declare no competing financial interests. 31
2
Acknowledgements: AJI and JFA are supported by the National Institute for Health Research 32
Imperial Biomedical Research Centre. BHM is supported by Imperial College Healthcare Charity 33
(grant number 161722). 34
3
Summary 35
Extensively drug-resistant organisms (XDRO) are a global threat to health. Colonisation with XDRO 36
prior to hematopoietic cell transplantation (HCT) frequently results in delayed delivery of 37
antimicrobials to which the organisms are susceptible and significantly increases non-relapse 38
mortality. Their inherent resistance to available antimicrobial agents coupled with a preponderance 39
to evolve further resistance makes biological approaches attractive. Suppression of pathogenic 40
organisms by fecal microbiome transplantation has previously been demonstrated, and here we 41
detail use of this approach to successfully supress XDRO prior to HCT that permitted an uneventful 42
transplant course in an otherwise high-risk situation. 43
4
Non-relapse mortality (NRM) of allogeneic hematopoietic cell transplantation (HCT) has 44
progressively fallen over the last four decades. Better supportive care, particularly in managing 45
infection has significantly contributed to the improved safety over that period. However, 46
antimicrobial resistance poses a significant global threat to health (1), and the emergence of 47
extensively drug-resistant organisms (XDRO) within HCT units now poses a direct threat to transplant 48
recipients (2). Gut colonisation with XDRO has been associated with an inased NRM (3) and 49
infections with XDRO during neutropenic periods are complex to manage and associated with a high 50
mortality (2). Innovative approaches in preventing and managing them are therefore necessary to 51
avoid reversing much of the progress made in limiting NRM over the last 4 decades. 52
A 63-year-old man presented to our institution with a new diagnosis of Philadelphia positive acute 53
lymphoblastic leukemia and received treatment following the UKALLXII trial schedule (4). He 54
achieved complete remission after induction chemotherapy together with imatinib. Following 55
intensification chemotherapy and continuous imatinib, allogeneic HCT was recommended to 56
consolidate his therapy. His treatment course was complicated by two separate episodes of 57
extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli bloodstream infections, two 58
episodes of Clostridium difficile infection (CDI), and central line-related methicillin sensitive 59
Staphylococcus aureus bacteremia. Each infection was successfully treated with antimicrobials, but 60
he was subsequently found to be colonised with a highly-resistant ges-5 carbapenemase-producing 61
Enterobacteriaceae (CPE), Klebsiella oxytoca, on routine rectal screening (table 1). 62
While gut colonisation with XDRO does not pose any significant risk per se, these organisms can 63
cause opportunistic infection during periods of prolonged neutropenia. Rates of spontaneous 64
clearance of these organism from colonised individuals are low, even in immunocompetent hosts, 65
ranging from 7-30% (5,6). Treatment options for elimination of XDRO from their site of origin within 66
the intestine are limited; non-absorbable antimicrobial agents often lead to only transient 67
suppression (5), and may precipitate the development of further resistance. Given the success of 68
donor fecal microbiota transplant (FMT) in the management of recurrent/refractory CDI (7), and the 69
apparently acceptable safety profile when used for CDI in the HCT setting (9), there is considerable 70
interest in the potential role of FMT in gut decontamination prior to HCT. Recipients of FMT for CDI 71
have been shown to have fewer antibiotic-resistant organisms within their gut microbiota following 72
transplantation (10) and there are emerging clinical reports of successful use of FMT in gut 73
decontamination of a variety of XDRO (including ESBL and CPE) (11), even in the setting of 74
haematological disorders (8). Therefore after discussion, this patient was offered FMT prior to 75
5
allogeneic HCT in an attempt to eradicate the XDRO and C. difficile from its intestinal niche, with the 76
aim of minimising his HCT NRM. 77
Following informed consent, the patient received gut preparation with four days of oral vancomycin 78
and neomycin, both 500mg four times daily. Antibiotics were stopped 24 hours prior to FMT 79
delivery, and preparation was completed with iso-osmotic bowel purgatives (Kleen Prep). The 80
unrelated donor stool was pre-screened, and negative for C. difficile PCR and toxin, as well as for 81
XDRO; other routine donor screening for transmissible infection was also negative (12). Preparation 82
of the transplant occurred immediately after stool donation under strict anaerobic conditions, using 83
an adapted version of a previously-described protocol (13) and stored at -80°C until required. The 84
FMT product comprised a thawed slurry of around 100ml homogenised stool preserved in a mixture 85
of glycerol and phosphate buffered saline (15:85, v/v) and was delivered via nasogastric tube. 86
Fasting was instituted six hours prior to receipt of the FMT, and treatment with a proton-pump 87
inhibitor (omeprazole) and pro-kinetic (metoclopramide) were administered one hour prior to FMT 88
delivery. The patient was allowed to eat and drink normally one-hour post-administration. Following 89
the procedure, he experienced mild nausea, loose stool and abdominal discomfort, which all 90
resolved after 24 hours without any specific intervention. Repeat rectal screening 7 days following 91
the FMT showed continued carriage of the ESBL E. coli but no evidence of ges-5 K. oxytoca CPE or C. 92
difficile. By day 16 after FMT neither the CPE nor ESBL were detected on rectal screening swabs 93
(Table 1). 94
Two weeks after FMT, the patient underwent a fludarabine (30mg/m2 D-7 to -3) and melphalan 95
(140mg/m2 day -2) conditioned reduced intensity sibling allogeneic HCT, with standard cyclosporine 96
and methotrexate graft-versus-host disease (GvHD) prophylaxis. The transplant course was 97
complicated by one episode of neutropenic fevers on day +5, with isolation of a fully-sensitive 98
Enterococcus faecalis from blood cultures (table 1). Empirical treatment with piperacillin-tazobactam 99
(4.5g three times daily), amikacin (15mg/kg once daily), teicoplanin (12mg/kg twice daily for three 100
doses, followed by 12mg/kg once daily) as per local policy with addition of colistin (3 million units 101
twice daily) resulted in prompt resolution of fever within 24 hours, and following isolation of the 102
sensitive organism antimicrobials were de-escalated to piperacillin-tazobactram and teicoplanin. A 103
second episode of neutropenic fever developed on day +10, and responded to a change in 104
antimicrobials from piperacillin-tazobactam to meropenem (1g three times daily), and cultures 105
remained sterile. Neutrophil engraftment was achieved on day +25 and the patient was discharged 106
from hospital on day +29. At day +100 he was well, with no evidence of leukemia, GvHD or XDRO by 107
rectal screening. At 12-months post-transplant the patient remains well and in remission. 108
6
Carbapenemase-producing micro-organisms are now endemic in a number of countries (1,14) and 109
the preponderance of these organism to extend their resistance spectrums is now contributing to 110
the emergence of strains resistance to our last resorts antimicrobials (15). A paucity in novel 111
antimicrobials means that current approaches are restricted to minimising the risk of XDRO 112
colonisation by antimicrobial stewardship and infection control, as well as managing clinical infection 113
with complex, and often more toxic, antimicrobial schedules. Novel strategies are therefore 114
required, and biological approaches would seem most favourable given the weaknesses of our 115
current pharmacological armoury. Resident gut commensals are adapted to the intestinal 116
microenvironment and have developed complex ecological networks upon which they have 117
subsequently become interdependent. Pathogens are equally reliant on their microenvironment, 118
and competition for critical nutrients, alteration of pH or oxygen tension, and production of toxic 119
metabolites are all mechanisms by which healthy commensals are capable of supressing pathogens 120
(16). While FMT has been reported in decontamination of XDRO in immunocompromised (17) 121
patients and those with blood disorders before (8) here we detail our use of this biological approach 122
in the suppression of XDROs in order to minimise NRM prior to allogeneic HCT. Our experience 123
supports the use of FMT in this setting as safe and tolerable, and warrants further study of efficacy in 124
a randomised fashion. The suppression of XDRO by FMT pre-HCT is particularly pertinent because 125
rather than simply identifying an addition risk factor for NRM, the presence of XDROs should been 126
considered a potentially modifiable risk factor, and this distinction is exceptionally important in risk 127
stratification. 128
129
130
7
Legend 131
Table 1. Microbiological sample results/Timeline. E.Coli, Escherichia coli, K. Oxytoca, Klebsiella 132
Oxytoca, S. aureus, staphylococcus aureus, E. Faecalis, Enterococcus faecalis, R, resistant, S, 133
susceptible, I, intermediate, C. difficle, Clostridium difficle, PCR, Polymerase chain reaction, HCT, 134
hematopoietic cell transplantation, XRDO, extensively drug-resistant organism. 135
136
8
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Contributions: AJI, BHM, FD, JRM, EM, JFA and JP conceived and implemented the treatment 193
strategy and prepared the manuscript. BHM performed the procedure with the assistance of FF and 194
GA, and the advice of JRM. All authors reviewed and revised the manuscript before approving the 195
final draft. 196
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